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Secreted factors from bone marrow stromal cells upregulate IL-10 and reverse acute kidney injury.

Milwid JM, Ichimura T, Li M, Jiao Y, Lee J, Yarmush JS, Parekkadan B, Tilles AW, Bonventre JV, Yarmush ML - Stem Cells Int (2012)

Bottom Line: Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease.Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI.In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

View Article: PubMed Central - PubMed

Affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, 51 Blossom Street, Boston, MA 02114, USA ; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative properties in vitro and in vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed that BMSC-CM causes IL-10 upregulation in treated animals, which is important to animal survival and protection of the kidney. In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

No MeSH data available.


Related in: MedlinePlus

IL-10 antibody abates the survival benefit of BMSC-CM-administered to rats undergoing lethal cisplatin AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), BMSC-conditioned medium (n = 14) or BMSC-conditioned medium containing 4 μg/mL neutralizing anti-rat IL-10 antibody (n = 10) were administered i.v. to the cisplatin AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to saline by Logrank test.
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fig7: IL-10 antibody abates the survival benefit of BMSC-CM-administered to rats undergoing lethal cisplatin AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), BMSC-conditioned medium (n = 14) or BMSC-conditioned medium containing 4 μg/mL neutralizing anti-rat IL-10 antibody (n = 10) were administered i.v. to the cisplatin AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to saline by Logrank test.

Mentions: Finally, to test the extent to which IL-10 may be responsible for the therapeutic effectiveness of the BMSC-CM treatment in AKI, we used the same survival model of cisplatin AKI (7.5 mg/kg) and coadministered BMSC-CM with neutralizing IL-10 antibody at 4 μg per dose. Figure 7 shows the diminished effect of BMSC-CM on the survival of animals when coadministered with neutralizing IL-10 antibody (n = 10) compared to the survival data presented in Figure 1: fewer animals survived when IL-10 antibody was coadministered with BMSC-CM. It should be noted that when tested for significance using the log rank test, the P value of the differences between BMSC-CM versus BMSC-CM with IL-10 antibody were 0.28, suggesting trends rather than significant increases or decreases in survival. Therefore, to further characterize the effect of IL-10 antibody on BMSC-CM administration, H&E histology was performed for the three treatment groups: saline (n = 3), BMSC-CM, (n = 3), or BMSC-CM with 4 μg of IL-10 antibody (n = 3). Staining for the kidney injury marker, KIM-1 and serum analysis of kidney injury markers BUN and creatinine were also performed on the same groups. BUN and creatinine were chosen as common markers of kidney injury, and KIM-1 was chosen as a more specific and sensitive marker of direct kidney injury [27, 37, 38]. H&E highlighted differences between the severity of tissue injury as a result of IL-10 neutralization (Figure 8(a)) and histological scoring revealed a distinction between the kidneys treated with BMSC-CM and those with IL-10 neutralizing antibody (Figure 8(b)). In all groups, the injury to the outer medulla was too severe to see a difference between the treatment arms; however, in the inner and outer cortex, BMSC-CM treated animals exhibited significantly less injury than vehicle-treated and BMSC-CM plus neutralizing IL-10 antibody treated. Supportive of the survival results, the injury evident from H&E staining among the antibody treated animals was as severe as those treated with vehicle. As these results are partially subjective, future studies that quantify the injury more completely might further elucidate the effect of IL-10 neutralization on tissue injury. Nevertheless, these same results were reflected in BUN and creatinine levels (Figure 9) and KIM-1 staining (Figure 10). BMSC-CM treated animals exhibited significantly less BUN and creatinine accumulation and minimal KIM-1-positive staining compared to the marked rise of BUN and creatinine and extensive positive KIM-1 staining of the kidney in vehicle treated and BMSC-CM plus IL-10 antibodies treated groups. Clearly these results support the hypothesis that IL-10 is an important mediator of BMSC-CM therapy and suggest that through IL-10 upregulation, BMSC-CM protects the kidney from injury during AKI.


Secreted factors from bone marrow stromal cells upregulate IL-10 and reverse acute kidney injury.

Milwid JM, Ichimura T, Li M, Jiao Y, Lee J, Yarmush JS, Parekkadan B, Tilles AW, Bonventre JV, Yarmush ML - Stem Cells Int (2012)

IL-10 antibody abates the survival benefit of BMSC-CM-administered to rats undergoing lethal cisplatin AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), BMSC-conditioned medium (n = 14) or BMSC-conditioned medium containing 4 μg/mL neutralizing anti-rat IL-10 antibody (n = 10) were administered i.v. to the cisplatin AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to saline by Logrank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig7: IL-10 antibody abates the survival benefit of BMSC-CM-administered to rats undergoing lethal cisplatin AKI. At hour 0, cisplatin dissolved in physiological saline (0.75 mg/mL) was administered i.p. to male, SAS-SD rats at a lethal dose (7.5 mg/kg). At hours 3, 9, 24, 48, and 72, 1 mL of either physiological saline (n = 12), BMSC-conditioned medium (n = 14) or BMSC-conditioned medium containing 4 μg/mL neutralizing anti-rat IL-10 antibody (n = 10) were administered i.v. to the cisplatin AKI rats. They were monitored for survival for 30 days. *P < 0.05 for BMSC-CM compared to saline by Logrank test.
Mentions: Finally, to test the extent to which IL-10 may be responsible for the therapeutic effectiveness of the BMSC-CM treatment in AKI, we used the same survival model of cisplatin AKI (7.5 mg/kg) and coadministered BMSC-CM with neutralizing IL-10 antibody at 4 μg per dose. Figure 7 shows the diminished effect of BMSC-CM on the survival of animals when coadministered with neutralizing IL-10 antibody (n = 10) compared to the survival data presented in Figure 1: fewer animals survived when IL-10 antibody was coadministered with BMSC-CM. It should be noted that when tested for significance using the log rank test, the P value of the differences between BMSC-CM versus BMSC-CM with IL-10 antibody were 0.28, suggesting trends rather than significant increases or decreases in survival. Therefore, to further characterize the effect of IL-10 antibody on BMSC-CM administration, H&E histology was performed for the three treatment groups: saline (n = 3), BMSC-CM, (n = 3), or BMSC-CM with 4 μg of IL-10 antibody (n = 3). Staining for the kidney injury marker, KIM-1 and serum analysis of kidney injury markers BUN and creatinine were also performed on the same groups. BUN and creatinine were chosen as common markers of kidney injury, and KIM-1 was chosen as a more specific and sensitive marker of direct kidney injury [27, 37, 38]. H&E highlighted differences between the severity of tissue injury as a result of IL-10 neutralization (Figure 8(a)) and histological scoring revealed a distinction between the kidneys treated with BMSC-CM and those with IL-10 neutralizing antibody (Figure 8(b)). In all groups, the injury to the outer medulla was too severe to see a difference between the treatment arms; however, in the inner and outer cortex, BMSC-CM treated animals exhibited significantly less injury than vehicle-treated and BMSC-CM plus neutralizing IL-10 antibody treated. Supportive of the survival results, the injury evident from H&E staining among the antibody treated animals was as severe as those treated with vehicle. As these results are partially subjective, future studies that quantify the injury more completely might further elucidate the effect of IL-10 neutralization on tissue injury. Nevertheless, these same results were reflected in BUN and creatinine levels (Figure 9) and KIM-1 staining (Figure 10). BMSC-CM treated animals exhibited significantly less BUN and creatinine accumulation and minimal KIM-1-positive staining compared to the marked rise of BUN and creatinine and extensive positive KIM-1 staining of the kidney in vehicle treated and BMSC-CM plus IL-10 antibodies treated groups. Clearly these results support the hypothesis that IL-10 is an important mediator of BMSC-CM therapy and suggest that through IL-10 upregulation, BMSC-CM protects the kidney from injury during AKI.

Bottom Line: Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease.Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI.In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

View Article: PubMed Central - PubMed

Affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, 51 Blossom Street, Boston, MA 02114, USA ; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative properties in vitro and in vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed that BMSC-CM causes IL-10 upregulation in treated animals, which is important to animal survival and protection of the kidney. In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

No MeSH data available.


Related in: MedlinePlus